This application, designed in response to RFA-DA-09-001, addresses the need for novel medications to manage cannabis dependence and addiction, recognized public health problems that are directly relevant to NIDA's mission. (-)-delta-9-Tetrahydrocannabinol (delta-9-THC), the principal active ingredient in illicitly smoked marijuana, is legally available in oral preparations (dronabinol) for the relief of pain and nausea associated with the occurrence or management of cancer or HIV/AIDS. Recently, it also has been shown to have positive effects in countering withdrawal symptoms that likely contribute to marijuana addiction and relapse. However, oral formulations of delta-9-THC suffer from a number of clinically unfavorable properties including poor bioavailability, erratic biodisposition, and unpredictable onsets and offsets of action. We propose to synthesize and efficiently identify novel cannabinoid agonists that will improve upon the pharmacological characteristics of delta-9-THC and that, consequently, may serve as viable medications for the management of cannabis dependence. In our chemistry program, we will modify delta-9-THC and nabilone to produce unique molecules that have improved 'druggability', i.e., increased polarity, water solubility, and designed for inactivation through enzymatic detoxification. In this 'soft drug' approach, the drug, after exercising its biological actions, is enzymatically inactivated to yield products with no or much lower activities. In our pharmacology program, we will use in vitro measures (receptor binding, functional efficacy, plasma and microsomal stability) and in vivo endpoints (brain penetrability, hypothermia, analgesia) to identify novel cannabinergic analogs that reliably enter the brain and have predictable time courses of action. Compounds with the most favorable preclinical characteristics will be evaluated in drug discrimination studies to gauge the presence and time course of THC-like 'subjective-like' effects. Finally, the most promising compounds will be given in repeated dosing regimens to evaluate their ability to counter withdrawal as well as their propensity to produce cannabinoid tolerance or dependence.